Secreted morphogens such as the Wnt family of signaling proteins control animal development including axis formation, patterning and cell movements, and regulate adult tissue homeostasis, stem cell renewal and regeneration (Clevers, 2006; Logan and Nusse, 2004; MacDonald et al., 2009; Moon et al., 2004). Deregulation of Wnt signaling in humans causes birth defects, cancer, osteoporosis and other diseases (Clevers, 2006; Logan and Nusse, 2004; MacDonald et al., 2009; Moon et al., 2004). As prototypic morphogens Wnt proteins exhibit both short and long range signaling properties and govern the behavior of responding cells in a concentration gradient field (Hausmann et al., 2007; Strigini and Cohen, 2000; Zecca et al., 1996). The mechanism that regulates Wnt biogenesis and gradient formation has been intensively studied but not been fully understood. Critical for Wnt biogenesis and functions are post-translational modifications including N-glycosylation and lipidation, as have been best exemplified for the mouse Wnt3a protein (Komekado et al., 2007; Takada et al., 2006; Willert et al., 2003). O-acylation of a serine residue (S209) and N-glycosylation appear to be required for Wnt3a secretion (Komekado et al., 2007; Takada et al., 2006), whereas a distinct lipid modification, palmitoylation of a cysteine residue (C77), is important for Wnt3a activity (Willert et al., 2003). These modifications have profound influence on Wnt trafficking through the secretory pathway, extracellular transport/distribution and/or receptor binding (Cong et al., 2004; Franch-Marro et al., 2008; Komekado et al., 2007; Kurayoshi et al., 2007; Takada et al., 2006; Willert et al., 2003; Zhai et al., 2004). Whether Wnt proteins can be post-translationally modified and inactivated in development and/or tissue homeostasis is unknown.
Canonical Wnt signaling plays a central role in metazoan anterior-posterior (AP) patterning (De Robertis and Kuroda, 2004; Niehrs, 2004; Petersen and Reddien, 2009). Wnt engagement of a cell surface receptor complex composed of the serpentine Frizzled (Fz) receptor and the single-span LDL receptor-related protein 6 (LRP6) induces the stabilization of the transcription co-activator beta-catenin (He et al., 2004; MacDonald et al., 2009), thereby activating gene expression programs for AP patterning. A gradient of Wnt/beta-catenin signaling occurs along the AP axis, with the highest level posteriorly (Kiecker and Niehrs, 2001). In the Xenopus embryo the dorsal Spemann-Mangold Organizer promotes head/anterior development via secreting Wnt antagonists such as secreted Fz-related proteins (sFRPs) and Dickkopf-1 (Dkk1), which bind to and inhibit Wnt/Fz or LRP6 to create an anterior zone free of Wnt signaling (De Robertis and Kuroda, 2004; Harland and Gerhart, 1997; Niehrs, 2004).